The infection of HHV-6 occurs very early in childhood (under one year) and the virus remains for life in a latent state. Using the peripheral mononuclear cells in culture from HIV-1-positive AIDS. chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE) patients and bone marrow transplant recipients, a high frequency of virus activation (40%) compared to normal donors (12%) was detected indicating active virus replication. HHV-6 was found to induce IL-1beta and TNF-alpha in human peripheral blood mononuclear cells. In contradistinction. HHV-6 has no effect on IL-6 induction. Cytokine induction appeared to be mediated by early viral protein. Cytokine production by HHV-6 in cells suggests how HHV-6 may contribute to disease manifestation. HHV-6 antigen-positive cells were detected by in situ hybridization and by monoclonal antibody assays in Hodgkin's disease, (HD). AIDS. SLE and Sjogren's syndrome patients' cells. The virus DNA-positive cells expressed CD38+, CD4+, and to a lower degree CD8+ and CD21+ cell receptors. Using ELISA and HHV-6 early protein (P41/38). sera from African Burkitt's lymphoma (ABL). HD and American Burkitt's lymphoma (AmBL) showed high frequency of antibody to P41/38 (ABL, 96.5%; HD, 62.5%) compared to normals (12%), whereas ELISA to HHV-6 late antigen (gpll0) failed to detect these differences. These findings indicated active HHV-6 replication and suggested a possible role of this virus in the pathogenesis of these malignancies. Thus. this assay may be a good marker for active and chronic HHV-6 infections.